Process and intermediates for preparing integrase inhibitors

ABSTRACT

The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

PRIORITY OF INVENTION

This application claims priority under 35 U.S.C. 119(e) from U.S.Provisional Patent Application No. 60/971,395, filed 11 Sep. 2007, thecontents of which are incorporated herein in their entirety.

BACKGROUND OF THE INVENTION

International Patent Application Publication Number WO 2004/046115provides certain 4-oxoquinolone compounds that are useful as HIVintegrase inhibitors. The compounds are reported to be useful asanti-HIV agents.

International Patent Application Publication Number WO 2005/113508provides certain specific crystalline forms of one of these4-oxoquinolone compounds,6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinolone-3-carboxylicacid. The specific crystalline forms are reported to have superiorphysical and chemical stability compared to other physical forms of thecompound.

There is currently a need for improved methods for preparing the4-oxoquinolone compounds reported in International Patent ApplicationPublication Number WO 2004/046115 and in International PatentApplication Publication Number WO 2005/113508. In particular, there is aneed for new synthetic methods that are simpler or less expensive tocarry out, that provide an increased yield, or that eliminate the use oftoxic or costly reagents.

SUMMARY OF THE INVENTION

The present invention provides new synthetic processes and syntheticintermediates that are useful for preparing the 4-oxoquinolone compoundsreported in International Patent Application Publication Number WO2004/046115 and in International Patent Application Publication NumberWO 2005/113508.

Accordingly, in one embodiment, the present invention provides a methodfor preparing a compound of formula 10

or a pharmaceutically acceptable salt thereof, in which a compound offormula 4

or a salt thereof is prepared and converted into a compound of formula10, characterized in that the compound of formula 4 is prepared from acompound of formula 15

or a salt thereof, by the steps of replacing the bromine atom with acarboxyl group, and replacing the hydroxyl group with a hydrogen atom.

In another embodiment the invention provides a compound of formula 15:

or a salt thereof.

In another embodiment the invention provides a method for preparing acompound of formula 15:

or a salt thereof comprising converting a corresponding compound offormula 14:

to the compound of formula 15 or the salt thereof.

In another embodiment the invention provides a compound of formula 15a:

that is useful as an intermediate for preparing the 4-oxoquinonecompounds.

In another embodiment the invention provides a compound of formula 16:

that is useful as an intermediate for preparing the 4-oxoquinonecompounds.

The invention also provides other synthetic processes and syntheticintermediates disclosed herein that are useful for preparing the4-oxoquinone compounds.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl denotes both straight and branchedgroups, but reference to an individual radical such as propyl embracesonly the straight chain radical, a branched chain isomer such asisopropyl being specifically referred to.

It will be appreciated by those skilled in the art that a compoundhaving a chiral center may exist in and be isolated in optically activeand racemic forms. Some compounds may exhibit polymorphism. It is to beunderstood that the present invention encompasses processes forpreparing any racemic, optically-active, polymorphic, tautomeric, orstereoisomeric form, or mixtures thereof, of a compound describedherein, it being well known in the art how to prepare optically activeforms (for example, by resolution of the racemic form byrecrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase).

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

Specifically, C₁-C₆alkyl can be methyl, ethyl, propyl, isopropyl, butyl,iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

A specific value for R_(a) is methyl.

A specific value for R_(b) is methyl.

A specific value for R_(c) is 1-imidazolyl.

A specific value for R is ethyl.

In one embodiment, the compound of formula 4 or a salt thereof isprepared by metalating the compound of formula 15 or a salt thereof andtreating with carbon dioxide to provide the compound of formula 3:

or a salt thereof, and then converting the compound of formula 3 into acompound of formula 4.

The compound of formula 15 or a salt thereof may be, for example, a saltof formula 15a

In another embodiment, the compound of formula 15 is converted into acompound of formula 16

which is then metalated and treated with carbon dioxide to afford acompound of formula 4.

It will be appreciated that the step of replacing the bromine atom witha carboxyl group is a carboxylation. This step may conveniently beeffected by metalation, for example, by treatment withisopropylmagnesium chloride or isopropylmagnesium chloride lithiumchloride complex, followed by treatment with carbon dioxide.

It will also be appreciated that the step of replacing the hydroxylgroup with a hydrogen atom is a dehydroxylation. This step may beeffected by treatment with a trialkylsilane, such as triethylsilane,conveniently in the presence of trifluoroacetic acid.

In another embodiment of the invention the compound of formula 15 or asalt thereof is converted to a compound of formula 3:

or a salt thereof. For example, the compound of formula 15 or a saltthereof can be converted to the compound of formula 3 or a salt thereofby metalating the compound of formula 15 or the salt thereof (e.g. bytreatment with isopropylmagnesium chloride) and treating with carbondioxide to provide the compound of formula 3 or the salt thereof.

In another embodiment of the invention the compound of formula 3 or thesalt thereof is converted to a compound of formula 4:

or a salt thereof.

In another embodiment of the invention the compound of formula 4 isconverted to a compound of formula 5′:

or a salt thereof, wherein R_(c) is a leaving group (such as halo or1-imidazolyl). The carboxylic acid functional group of Compound 4 can beconverted to an activated species, for example an acid chloride or anacyl imidazolide (Compound 5′) by treatment with a suitable reagent,such as, for example, thionyl chloride, oxalyl chloride, cyanuricchloride or 1,1′-carbonyldiimidazole in a suitable solvent (e.g.,toluene or tetrahydrofuran). Any suitable leaving group R_(c) can beincorporated into the molecule, provided the compound of formula 5′ canbe subsequently converted to a compound of formula 6. The reaction canconveniently be carried out using about 1 equivalent of1,1′-carbonyldiimidazole in tetrahydrofuran. In one embodiment, thecompound of formula 5′ is a compound of formula 5a.

The compound of formula 4 may be converted to the compound of formula 5aby treatment with 1,1′-carbonyldiimidazole.

In another embodiment of the invention a compound of formula 5′ or asalt thereof, can be converted to a compound of formula 6:

or a salt thereof, wherein R is C₁-C₆alkyl. In one embodiment, thecompound of formula 5′ is converted to the compound of formula 6 bytreatment with the corresponding mono-alkylmalonate salt. An example ofa mono-alkylmalonate salt is potassium monoethylmalonate. For example, acompound of formula 5′ can be combined with about 1 to 5 equivalents ofa monoalkyl malonate salt and about 1 to 5 equivalents of a magnesiumsalt in a suitable solvent. Conveniently, a compound of formula 5′ canbe combined with about 1.7 equivalents of potassium monoethyl malonateand about 1.5 equivalents of magnesium chloride. A suitable base, forexample triethylamine or imidazole, can be added to the reaction. Thereaction can conveniently be carried out at an elevated temperature(e.g., about 100±50° C.) and monitored for completion by any suitabletechnique (e.g., by HPLC). Upon completion of the reaction, Compound 6can be isolated using any suitable technique (e.g., by chromatography orcrystallization).

In another embodiment of the invention the compound of formula 6 or asalt thereof, can be converted to a corresponding compound of formula 7:

wherein R_(a) and R_(b) are each independently C₁-C₆alkyl; and R isC₁-C₆alkyl. Compound 6 can be converted to an activated alkylideneanalog, such as Compound 7, by treatment with a formate group donor suchas a dimethylformamide dialkyl acetal (e.g., dimethylformamide dimethylacetal) or a trialkylorthoformate. The reaction can be carried out atelevated temperature (e.g., about 100±50° C.). This reaction may beaccelerated by the addition of an acid catalyst, such as, for example,an alkanoic acid, a benzoic acid, a sulfonic acid or a mineral acid.About 500 ppm to 1% acetic acid can conveniently be used. The progressof the reaction can be monitored by any suitable technique (e.g., byHPLC). Compound 7 can be isolated or it can be used directly to preparea compound of formula 8 as described below.

In another embodiment of the invention the compound of formula 7 can beconverted to a corresponding compound of formula 8:

wherein R is C₁-C₆alkyl. Compound 7 can be combined with(S)-2-amino-3-methyl-1-butanol (S-Valinol, about 1.1 equivalents) toprovide compound 8. The progress of the reaction can be monitored by anysuitable technique (e.g., by HPLC). The compound of formula 8 can beisolated or used directly to prepare a compound of formula 9 asdescribed below.

In another embodiment, the invention provides a method for preparing acompound of formula 9:

wherein R is C₁-C₆alkyl, comprising cyclizing a corresponding compoundof formula 8:

Compound 8 can be cyclized to provide Compound 9 by treatment with asilylating reagent (e.g., N,O-bis(trimethylsilyl)acetamide,N,O-bis(trimethylsilyl)trifluoroacetamide or hexamethyldisilazane). Thereaction can be conducted in a polar aprotic solvent (e.g.,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone oracetonitrile). A salt (e.g., potassium chloride, lithium chloride,sodium chloride or magnesium chloride) can be added to accelerate thereaction. Typically, about 0.5 equivalents of a salt such as potassiumchloride is added. The reaction may be conducted at elevated temperature(e.g., a temperature of about 100±20° C.) if necessary to obtain aconvenient reaction time. The progress of the reaction can be monitoredby any suitable technique (e.g., by HPLC). During the workup, an acidcan be used to hydrolyze any silyl ethers that form due to reaction ofthe silylating reagent with the alcohol moiety of compound 8. Typicalacids include mineral acids, sulfonic acids, or alkanoic acids. Onespecific acid that can be used is aqueous hydrochloric acid. Uponcompletion of the hydrolysis, Compound 9 can be isolated by any suitablemethod (e.g., by chromatography or by crystallization). In the aboveconversion, the silating reagent transiently protects the alcohol and issubsequently removed. This eliminates the need for separate protectionand deprotection steps, thereby increasing the efficiency of theconversion.

In another embodiment of the invention the compound of formula 9 isconverted to a compound of formula 10:

Compound 9 can be converted to Compound 10 by treatment with a suitablebase (e.g., potassium hydroxide, sodium hydroxide or lithium hydroxide).For example, about 1.3 equivalents of potassium hydroxide canconveniently be used. This reaction may be conducted in any suitablesolvent, such as, for example, tetrahydrofuran, methanol, ethanol orisopropanol, or a mixture thereof. The solvent can also include water. Amixture of isopropanol and water can conveniently be used. The progressof the reaction can be monitored by any suitable technique (e.g., byHPLC). The initially formed carboxylate salt can be neutralized bytreatment with an acid (e.g., hydrochloric acid or acetic acid). Forexample, about 1.5 equivalents of acetic acid can conveniently be used.Following neutralization, Compound 10 can be isolated using any suitabletechnique (e.g., by chromatography or crystallization).

In another embodiment of the invention the compound of formula 10 can becrystallized by adding a seed crystal to a solution that comprises thecompound of formula 10. International Patent Application PublicationNumber WO 2005/113508 provides certain specific crystalline forms of6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinolone-3-carboxylicacid. The entire contents of International Patent ApplicationPublication Number WO 2005/113508 is incorporated herein by reference(in particular, see pages 12-62 therein). The specific crystalline formsare identified therein as Crystal Form II and Crystal Form III. Crystalform II has an X-ray powder diffraction pattern having characteristicdiffraction peaks at diffraction angles 2θ(°) of 6.56, 13.20, 19.86,20.84, 21.22, and 25.22 as measured by an X-ray powder diffractometer.Crystal form III has an X-ray powder diffraction pattern havingcharacteristic diffraction peaks at diffraction angles 2θ(°) of 8.54,14.02, 15.68, 17.06, 17.24, 24.16, and 25.74 as measured by an X-raypowder diffractometer. International Patent Application PublicationNumber WO 2005/113508 also describes how to prepare a crystalline formof6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinolone-3-carboxylicacid that have an extrapolated onset temperature of about 162.1° C., aswell as how to prepare a seed crystal having a purity of crystal of notless than about 70%. Accordingly, seed crystals of6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinolone-3-carboxylic acid can optionally be prepared as described in InternationalPatent Application Publication Number WO 2005/113508. Advantageously,the process illustrated in Scheme I below provides a crude mixture ofCompound 10 that can be directly crystallized to provide Crystal FormIII without additional purification (e.g. without the prior formation ofanother polymorph such as Crystal Form II, or without some other form ofprior purification), see Example 6 below.

In cases where compounds identified herein are sufficiently basic oracidic to form stable acid or base salts, the invention also providessalts of such compounds. Such salts may be useful as intermediates, forexample, for purifying such compounds. Examples of useful salts includeorganic acid addition salts formed with acids, for example, tosylate,methanesulfonate, acetate, citrate, malonate, tartarate, succinate,benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitableinorganic salts may also be formed, including hydrochloride, sulfate,nitrate, bicarbonate, and carbonate salts.

Salts may be obtained using standard procedures well known in the art,for example by reacting a sufficiently basic compound such as an aminewith a suitable acid affording an anion. Alkali metal (for example,sodium, potassium, or lithium) or alkaline earth metal (for examplecalcium or magnesium) salts of carboxylic acids, for example, can alsobe made.

The invention will now be illustrated by the following non-limitingExamples.

An integrase inhibitor of formula 10 can be prepared as illustrated inthe following Scheme 1.

Example 1 Preparation of Compound 3

Compound 14 (10 g) was combined with 28 mL of THF and 9 mL ofbisdimethylaminoethyl ether before being cooled to 0° C.Isopropylmagnesium chloride (22.9 mL of a 2.07 M solution in THF) wasadded and the mixture was allowed to warm to room temperature overnight.Additional isopropylmagnesium chloride (5 mL) was added to improveconversion before 3-chloro-2-fluorobenzaldehyde (4.4 mL) was added.After stirring at ambient temperature for 2 hours 38.6 g of a 14 wt %THF solution of isopropylmagnesium chloride lithium chloride complex wasadded. After stirring overnight at ambient temperature CO₂ gas wasbubbled into the reaction mixture. When conversion was complete thereaction was quenched to pH<3 with 2 M hydrochloric acid. The phaseswere separated and the organic phase was extracted with ethyl acetate.The combined organic layers were washed with saturated aqueous sodiumchloride. The organic phase was concentrated and the productprecipitated by the addition of MTBE. The slurry was filtered and theproduct air dried to yield Compound 3: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.15(br s, 1H), 7.81 (s, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.26 (t, J=6.8 Hz,1H), 7.15 (t, J=7.8 Hz, 1H), 6.77 (s, 1H), 6.09 (d, J=4.7 Hz, 1H), 5.90(d, J=4.9 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H).

Example 2 Preparation of Compound 4

Triethylsilane (6.83 g) was added to trifluoroacetic acid (33.13 g) thathad been pre-cooled in an ice bath. Compound 3 (10 g) was added to themixture keeping the temperature below 15° C. After stirring for 2 h MTBEwas added to precipitate the product. The slurry was filtered and theproduct washed with additional MTBE. After drying, 9.12 g of Compound 4was isolated: ¹H NMR (DMSO-d₆, 400 MHz) δ 12.11 (br s, 1H), 7.47 (s,1H), 7.42-7.38 (m, 1H), 7.14-7.08 (m, 2H), 6.67 (s, 1H), 3.87-3.84 (m,8H).

Alternatively, Compound 4 can be prepared as follows.

Triethylsilane (7.50 g) was added to trifluoroacetic acid (49.02 g) thathad been pre-cooled in an ice bath. Compound 3 (14.65 g) was added tothe mixture keeping the temperature below 15° C. After stirring for 1 ha solution of 17.63 g sodium acetate in 147 mL methanol was added. Themixture was heated to reflux for 3 hours then cooled to 0° C. The slurrywas filtered and the product washed with additional methanol. Afterdrying 12.3 g of Compound 4 (89.7% yield) was isolated: ¹H NMR (DMSO-d₆,400 MHz) δ 12.11 (br s, 1H), 7.47 (s, 1H), 7.42-7.38 (m, 1H), 7.14-7.08(m, 2H), 6.67 (s, 1H), 3.87-3.84 (m, 8H).

Example 3 Preparation of Compound 5a

Imidazole (0.42 g) and 1,1′-carbonyldiimidazole (5.49 g) were slurriedin 30 mL of THF at ambient temperature. Compound 4 (10 g) was added inone portion and the mixture was stirred at ambient temperature until thereaction was complete by HPLC. The resulting slurry was filtered and thesolids washed with MTBE. The solids were dried to yield Compound 5a: ¹HNMR (DMSO-d₆, 400 MHz) δ 7.99 (s, 1H), 7.52 (s, 1H), 7.41-7.38 (m, 1H),7.30 (s, 1H), 7.12-7.08 (m, 2H), 7.04 (s, 1H), 6.81 (s, 1H), 3.91 (s,2H), 3.90 (s, 3H), 3.79 (s, 3H).

Example 4 Preparation of Compound 6a

Imidazole (0.42 g) and 1,1′-carbonyldiimidazole (5.49 g) were slurriedin 30 mL of THF at ambient temperature. Compound 5a (10 g) was added inone portion and the mixture was stirred at ambient temperature for 4hours to form a slurry of compound 5a. In a separate flask, 8.91 g ofpotassium monoethyl malonate was slurried in 40 mL of THF. Magnesiumchloride (4.40 g) was added and the resulting slurry was warmed to 55°C. for 90 minutes. The slurry of Compound 5a was transferred to themagnesium chloride/potassium monoethyl malonate mixture and stirred at55° C. overnight. The mixture was then cooled to room temperature andquenched by the dropwise addition of 80 mL of 28 wt % aqueous H₃PO₄. Thephases were separated and the organic phase was washed successively withaqueous NaHSO₄, KHCO₃ and NaCl solutions. The organic phase wasconcentrated to an oil and then coevaporated with ethanol. The resultingsolid was dissolved in 30 mL ethanol and 6 mL water. Compound 6a wascrystallized by cooling. The solid was isolated by filtration and theproduct was washed with aqueous ethanol. After drying Compound 6a wasobtained: ¹H NMR (DMSO-d₆, 400 MHz) δ 7.51 (s, 1H), 7.42-7.38 (m, 1H),7.12-7.10 (m, 2H), 6.70 (s, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.89 (s, 8H),3.81 (s, 2H), 1.15 (t, J=7.0 Hz, 3H).

Alternatively, Compound 6a can be prepared as follows.

Carbonyldiimidazole (10.99 g) was slurried in 60 mL of THF at ambienttemperature. Compound 4 (20 g) was added in one portion and the mixturewas stirred at ambient temperature for 30 min to form a slurry ofcompound 5. In a separate flask 15.72 g of potassium monoethyl malonatewas slurried in 100 mL of THF. Magnesium chloride (6.45 g) was added andthe resulting slurry was warmed to 55° C. for 5 hours. The slurry ofCompound 5 was transferred to the magnesium chloride/potassium monoethylmalonate mixture and stirred at 55° C. overnight. The mixture was thencooled to room temperature and quenched onto 120 mL of 28 wt % aqueousH₃PO₄. The phases were separated and the organic phase was washedsuccessively with aqueous KHCO₃ and NaCl solutions. The organic phasewas concentrated to an oil and then coevaporated with ethanol. Theresulting solid was dissolved in 100 mL ethanol and 12 mL water.Compound 6a was crystallized by cooling. The solid was isolated byfiltration and the product was washed with aqueous ethanol. After drying21.74 g Compound 6a (89% yield) was obtained: ¹H NMR (DMSO-d₆, 400 MHz)δ 7.51 (s, 1H), 7.42-7.38 (m, 1H), 7.12-7.10 (m, 2H), 6.70 (s, 1H), 4.06(q, J=7.0 Hz, 2H), 3.89 (s, 8H), 3.81 (s, 2H), 1.15 (t, J=7.0 Hz, 3H).

Example 5 Preparation of Compound 9a

Compound 6a (20 g) was stirred with 6.6 g dimethylformamide dimethylacetal, 66 g toluene and 0.08 g glacial acetic acid. The mixture waswarmed to 90° C. for 4 hours. The mixture was then cooled to ambienttemperature and 5.8 g (S)-2-amino-3-methyl-1-butanol was added. Themixture was stirred at ambient temperature for 1 hour before beingconcentrated to a thick oil. Dimethylformamide (36 g), potassiumchloride (1.8 g) and bis(trimethylsilyl)acetamide (29.6 g) were addedand the mixture was warmed to 90° C. for 1 h. The mixture was cooled toroom temperature and diluted with 200 g dichloromethane. Dilutehydrochloride acid (44 g, about 1N) was added and the mixture stirred atambient temperature for 20 min. The phases were separated and theorganic phase was washed successively with water, aqueous sodiumbicarbonate and water. The solvent was exchanged to acetonitrile and thevolume was adjusted to 160 mL. The mixture was heated to clarity, cooledslightly, seeded and cooled to crystallize Compound 9a. The product wasisolated by filtration and washed with additional cold acetonitrile.Vacuum drying afforded Compound 9a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.61 (s,1H), 7.86 (s, 1H), 7.45 (t, J=7.4 Hz, 1H), 7.26 (s, 1H), 7.23-7.14 (m,2H), 5.10 (br s, 1H), 4.62 (br s, 1H), 4.18 (q, J=7.0 Hz, 2H), 4.03 (s,2H), 3.96 (s, 3H), 3.92-3.84 (m, 1H), 3.78-3.75 (m, 1H), 2.28 (br s,1H), 1.24 (t, J=7.0 Hz, 3H), 1.12 (d, J=6.4 Hz, 3H), 0.72 (d, J=6.4 Hz,3H).

Alternatively, Compound 9a can be prepared as follows.

Compound 6a (50 g) was stirred with 17.5 g dimethylformamide dimethylacetal, 90 g DMF and 0.2 g glacial acetic acid. The mixture was warmedto 65° C. for 3 hours. The mixture was then cooled to ambienttemperature and 14.5 g (S)-2-amino-3-methyl-1-butanol and 25 g toluenewere added. The mixture was stirred at ambient temperature overnightbefore being concentrated by distillation. Potassium chloride (4.5 g)and bis(trimethylsilyl)acetamide (80.2 g) were added and the mixture waswarmed to 90° C. for 2 h. The mixture was cooled to room temperature anddiluted with 250 g dichloromethane. Dilute hydrochloride acid (110 g of˜1N) was added and the mixture stirred at ambient temperature for 30min. The phases were separated and the organic phase was washedsuccessively with water, aqueous sodium bicarbonate and water. Thesolvent was exchanged to acetonitrile by distillation. The mixture washeated to clarity, cooled slightly, seeded and cooled to crystallizeCompound 9a. The product was isolated by filtration and washed withadditional cold acetonitrile. Vacuum drying afforded 48.7 g (81% yield)of Compound 9a: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.61 (s, 1H), 7.86 (s, 1H),7.45 (t, J=7.4 Hz, 1H), 7.26 (s, 1H), 7.23-7.14 (m, 2H), 5.10 (br s,1H), 4.62 (br s, 1H), 4.18 (q, J=7.0 Hz, 2H), 4.03 (s, 2H), 3.96 (s,3H), 3.92-3.84 (m, 1H), 3.78-3.75 (m, 1H), 2.28 (br s, 1H), 1.24 (t,J=7.0 Hz, 3H), 1.12 (d, J=6.4 Hz, 3H), 0.72 (d, J=6.4 Hz, 3H).

Example 6 Preparation of Compound 10

Compound 9a (6.02 g) was slurried in 36 mL isopropanol and 24 mL ofwater. Aqueous potassium hydroxide (2.04 g of 45 wt % solution) wasadded and the mixture warmed to 40° C. After 3 hours 1.13 g glacialacetic acid was added the mixture seeded with 10 mg of Compound 10. Themixture was cooled in an ice bath for 2 hours and the solid was isolatedby filtration. The cake was washed with aqueous isopropanol and dried togive Compound 10: ¹H NMR (DMSO-d₆, 400 MHz) δ 15.42 (s, 1H), 8.87 (s,1H), 8.02 (s, 1H), 7.48-7.45 (m, 2H), 7.23 (t, J=6.8 Hz, 1H), 7.17 (t,J=7.8 Hz, 1H), 5.18 (br s, 1H), 4.86 (br s, 1H), 4.10 (s, 2H), 4.02 (s,3H), 3.97-3.96 (m, 1H), 3.79-3.76 (m, 1H), 2.36 (br s, 1H), 1.14 (d,J=6.3 Hz, 3H), 0.71 (d, J=6.3 Hz, 3H).

Alternatively, Compound 10 can be prepared from Compound 4 as describedin the following illustrative Examples 7-9.

Example 7 Preparation of a Compound of Formula 6a

Carbonyldiimidazole and imidazole are combined with anhydroustetrahydrofuran. Compound 4 is added to this mixture to form Compound 5and the reaction is monitored by HPLC. In a separate reactor potassiummonoethylmalonate is combined with tetrahydrofuran before anhydrousmagnesium chloride is added while maintaining the temperature NMT 30° C.The resulting slurry is warmed to 50° C. and held for at least two hoursbefore the Compound 5 mixture is added. The reaction is monitored byHPLC. Once the formation of Compound 5 is complete, the mixture iscooled to 18 to 25° C. and added to aqueous phosphoric acid to quench.The organic phase is washed with aqueous sodium bisulfate, brine,potassium bicarbonate and brine solutions before being polish filtered.The solvent is exchanged for anhydrous ethanol. Water is added and themixture is warmed to dissolve solids, cooled to about 40° C., seededwith Compound 6a and cooled to 0 to 5° C. The product is filtered,washed with cold aqueous ethanol and dried at NMT 40° C. to yieldCompound 6a.

Material M.W. Wt. Ratio Mole Ratio Compound 4 324.73 1.000 1.00 THF72.11 7.11 Imidazole 68.08 0.042 0.20 CDI 162.15 0.55 1.10 KEM 170.20.89 1.70 MgCl₂ 95.21 0.44 1.50 H₃PO₄ (85 wt %) 98.00 2.3 NaHSO₄ 120.060.24 KHCO₃ 100.12 0.50 NaCl 58.44 0.48 SDA 2B-2 EtOH (0.5% heptane)46.07 ~10 kgProcedure:

-   -   1. Charge 0.55 kg CDI and 0.042 kg imidazole to reactor 1.    -   2. Charge 2.67 kg THF to reactor 1 and agitate to form a slurry.    -   3. Charge 1.00 kg Compound 4 to reactor 1 in portions to        moderate the CO₂ offgas. This addition is endothermic    -   4. Charge 0.89 kg KEM to reactor 2.    -   5. Charge 4.45 kg THF to reactor 2 and agitate to form a slurry.    -   6. Charge 0.44 kg MgCl₂ to reactor 2 (can be added in portions        to moderate exotherm).    -   7. Warm the contents of reactor 2 to 50° C. and agitate at that        temperature for at least two hours.    -   8. Transfer the contents of reactor 1 to reactor 2. Mixture will        become thick temporarily if transferred very rapidly.    -   9. Agitate the contents of reactor 2 for at least 12 hours at        50° C.    -   10. Cool the slurry to ambient temperature.    -   11. Quench the reaction by transferring the reaction mixture        onto 7.0 kg of 28 wt % aqueous H₃PO₄ (2.3 kg 85 wt % H₃PO₄        dissolved in 4.7 kg H₂O). This addition is exothermic. Final pH        of aqueous layer should be 1-2.    -   12. Wash the organic (top) phase with 1.2 kg of 20 wt % aqueous        NaHSO₄ (0.24 kg of NaHSO₄ dissolved in 0.96 kg H₂O). Final pH of        aqueous layer should be 1-2.    -   13. Wash the organic (top) phase with 1.2 kg of 20 wt % aqueous        NaCl (0.24 kg of NaCl dissolved in 0.96 kg H₂O)    -   14. Wash the organic (top) phase with 5.0 kg of 10 wt % aqueous        KHCO₃ (0.50 kg of KHCO₃ dissolved in 4.5 kg H₂O). Final pH of        aqueous layer should be 8-10.    -   15. Wash the organic (top) phase with 1.2 kg of 20 wt % aqueous        NaCl (0.24 kg of NaCl dissolved in 0.96 kg H₂O). Final pH of        aqueous layer should be 7-9.    -   16. Concentrate the organic phase and exchange the solvent to        EtOH.    -   17. Adjust the concentration to ˜3.5 L/kg input.    -   18. Charge 0.6 volumes of water.    -   19. Warm 70-80° C. to form a clear solution.    -   20. Cool to 40° C. and seed with 0.1 wt % Compound 6.    -   21. Cool slowly to 5° C.    -   22. Hold for at least 2 hours.    -   23. Filter and wash the cake with two 1.35 kg volume portions of        50:50 EtOH:H₂O (1.2 kg EtOH combined with 1.5 kg H₂O).    -   24. Dry the cake at less than 50° C.

Example 8 Preparation of a Compound of Formula 9a

Compound 6a is combined with toluene, N,N-dimethylformamide dimethylacetal and glacial acetic acid before being warmed to 100° C. Thereaction is monitored by HPLC. Once the formation of Compound 7a iscomplete the mixture is cooled to 18 to 25° C. before (5)-(+)-valinol isadded. The reaction is monitored by HPLC. Once the formation of Compound8a is complete the mixture is concentrated. The residue is combined withdimethylformamide, potassium chloride and N,O-bistrimethylsilylacetamide and warmed to 100° C. The reaction is monitored by HPLC. Oncecomplete the mixture is cooled and dichloromethane is added. Aqueoushydrochloric acid is added to desilylate Compound 9a. This reaction ismonitored by TLC. Once complete the organic phase is washed with water,aqueous sodium bicarbonate and water. The solvent is exchanged foracetonitrile and the mixture warmed. The mixture is seeded and cooled tocrystallize Compound 9a. The product is filtered, washed with coldacetonitrile and dried at NMT 40° C. to yield Compound 9a.

Material M.W. Wt. Ratio Mole Ratio Compound 6a 394.82 1.00 1.00 Toluene92.14 4.3 Glacial acetic acid 60.05 0.001 0.007 N,N-dimethylformamidedimethyl 119.16 0.33 1.1 acetal (S)-(+)-Valinol 103.16 0.29 1.1 DMF73.10 1.8 KCl 74.55 0.09 0.5 N,O-bis(trimethylsilyl)acetamide 203.431.13 2.2 1N HCl 36.5 2.0 DCM 84.93 10 Water 18.02 8 5% Aq. NaHCO₃ 84.014 CAN 41.05 QS Compound 9a seeds 475.94 0.005

-   -   1. Charge Reactor 1 with 1.00 kg Compound 6a.    -   2. Charge 0.33 kg N,N-dimethylformamide dimethyl acetal (1.1        eq), 0.001 kg glacial acetic acid and 3.3 kg toluene to Reactor        1.    -   3. Warm the mixture to ˜100° C. (note that some MeOH may distill        during this operation).    -   4. After 1 h the reaction should be complete by HPLC (˜2%        Compound 6a apparently remaining)¹.    -   5. Cool the mixture in Reactor 1 to 18-25° C.    -   6. Charge 0.29 kg (S)-(+)-Valinol (1.1 eq) dissolved in 1.0 kg        toluene to Reactor 1 and continue agitation at ambient        temperature.    -   7. After 1 h the reaction should be complete by HPLC (<1%        Compound 6a).    -   8. Concentrate the contents of Reactor 1 to ˜2 L/kg.    -   9. Charge 1.8 kg DMF, 0.09 kg potassium chloride (0.5 eq,) and        1.13 kg N,O-bistrimethylsilyl acetamide (2.2 eq.) to Reactor 1.    -   10. Warm the mixture in Reactor 1 to ˜100° C.    -   11. Reaction should be complete in ˜1 h (˜5% Compound 8a        remaining).    -   12. Cool the contents of Reactor 1 to 18-25° C.    -   13. Charge 10 kg DCM to Reactor 1.    -   14. Charge 2.0 kg 1 N aqueous HCl to Reactor 1 over ˜15 min,        maintaining the temperature of the mixture<35° C.    -   15. Agitate the mixture for at least 10 min to desilylate        Compound 8a. Monitor the progress of desilylation by TLC.²    -   16. Separate the phases.    -   17. Wash the organic phase with 4.0 kg water.    -   18. Wash the organic phase with 4.0 kg 5% aqueous sodium        bicarbonate.    -   19. Wash the organic phase with 4.0 kg water.    -   20. Concentrate the organic phase by distillation to ˜1.5 L/kg        Compound 6a.    -   21. Solvent exchange to ACN by distillation until a slurry is        formed. Adjust the final volume to ˜8 L/kg Compound 6a.    -   22. Heat the mixture to reflux to redissolve the solid.    -   23. Cool the solution to 75° C. and charge Compound 9a seeds.    -   24. Cool the mixture to 0° C. over at least 2 h and hold at that        temperature for at least 1 h.    -   25. Isolate Compound 9a by filtration and wash the wet cake with        1.6 kg cold ACN.    -   26. Dry the wet cake at <40° C. under vacuum.        Notes:    -   1. The HPLC AN of remaining Compound 6a is exaggerated by a        baseline artifact. The HPLC in step shows only 2% of Compound 6a        relative to Compound 8a. Experiments demonstrated that adding        more reagent and extending reaction time typically will not        further reduce the observed level of Compound 6a.    -   2. TLC method:        -   Eluting solvent: 100% ethyl acetate,        -   Silylated Compound 9a Rf: 0.85, Compound 9a Rf: 0.50.

Example 9 Preparation of a Compound of Formula 10

Compound 9a is combined with aqueous isopropyl alcohol and warmed to 30to 40° C. Aqueous potassium hydroxide is added and the reaction ismonitored by HPLC. Once complete, glacial acetic acid is added and themixture warmed to 60 to 70° C. The solution is hot filtered and cooledto 55 to 65° C. The solution is seeded (see International PatentApplication Publication Number WO 2005/113508) and cooled to 0° C. Theproduct is isolated by filtration, washed with cold aqueous isopropylalcohol and dried at NMT 50° C. to yield Compound 10.

Material M.W. Wt. Ratio Mole Ratio Compound 9a 475.94 1.00 1.00Isopropyl alcohol 60.10 4.7 Water 18.02 4.0 45% KOH 56.11 0.34 1.3Glacial Acetic Acid 60.05 0.19 1.50 Compound 10 seeds 447.88 0.01

-   -   1. Charge 1.00 kg Compound 9a to Reactor 1.    -   2. Charge 4.7 kg isopropyl alcohol and 4.0 kg water to Reactor        1.    -   3. Charge 0.34 kg 45% aqueous KOH to Reactor 1.    -   4. Warm the mixture in Reactor 1 to 30-40° C.    -   5. When hydrolysis is complete add 0.19 kg of glacial acetic        acid.    -   6. Warm the mixture to 60-70° C. and polish filter the solution        to Reactor 2.    -   7. Cool the mixture in Reactor 2 to 55-65° C.    -   8. Seed with Compound 10 (see International Patent Application        Publication Number WO 2005/113508) as a slurry in 0.28 volumes        of 6:4 isopropyl alcohol:water.    -   9. Cool the mixture to 18-25° C. over at least 2 h and agitate        to form a slurry.    -   10. Cool the mixture to 0° C. and agitate for at least 2 h.    -   11. Isolate Compound 10 by filtration and wash the cake with 3×1        S cold isopropyl alcohol:water (6:4) solution.    -   12. Dry the isolated solids at <50° C. under vacuum.

Example 10 Preparation of Compound 15

Bisdimethylaminoethyl ether (2.84 g) was dissolved in 42 mL THF andcooled in an ice bath. Isopropylmagnesium chloride (8.9 mL of a 2 Msolution in THF) followed by Compound 14 (5 g dissolved in 5 mL THF)were added slowly sequentially. The mixture was allowed to warm toambient temperature and stirred overnight. Next, 2.1 mL of3-chloro-2-fluorobenzaldehyde was added. After stirring for ˜1 h, themixture was quenched to pH˜7 with 2N HCl. The product was extracted intoethyl acetate and the organic phase was dried over sodium sulfate. Thesolvent was exchange to heptane to precipitate the product and a mixtureof heptanes:MTBE (4:1) was added to form a slurry. After filtration thesolid was slurried in toluene, filtered and vacuum dried to yieldcompound 15: ¹H NMR (CD₃CN, 400 MHz) δ 7.47 (s, 1H), 7.41-7.35 (m, 2H),7.15 (t, J=7.4 Hz, 1H), 6.66 (s, 1H), 6.21 (br s, 1H), 3.90 (s, 3H),3.87 (br s, 1H), 3.81 (s, 3H).

Example 11 Preparation of Compound 15a

Compound 14 (5 g), isopropylmagnesium chloride (8.9 mL of 2M solution inTHF) and THF (56 mL) were combined at ambient temperature and thenwarmed to 50° C. for ˜5 hours. After cooling to ambient temperature andstirring overnight, 2.1 mL of 3-chloro-2-fluorobenzaldehyde was addeddropwise to form a slurry. After stirring overnight the solid wasisolated by filtration and washing with MTBE to yield compound 15a.

Example 12 Preparation of Compound 16

Triethylsilane (1.2 mL) was added to trifluoroacetic acid (2.3 mL) thathad been pre-cooled in an ice bath. Compound 15 (1.466 g) was added tothe mixture keeping the temperature below 5° C. After stirring for ˜2 hice was added to quench the reaction. The product was extracted with DCMand the organic phase was washed with aq. NaHCO₃. The organic phase wasdried over Na₂SO₄ and concentrated to dryness. The product was purifiedby silica gel column chromatography to provide 1.341 g of Compound 16:¹H NMR (CDCl₃, 400 MHz) δ 7.20 (t, J=7.0 Hz, 1H), 6.99-6.91 (m, 3H),6.46 (s, 1H), 3.91 (s, 3H), 3.81 (s, 5H).

The compound of formula 16 can be carboxylated to provide a compound ofFormula 4 following a method analogous to that described in Example 1.

Example 13 Alternative Preparation of a Compound of Formula 3

Compound 14 is combined with anhydrous tetrahydrofuran:dioxane (5:0.9),and the mixture is agitated under a nitrogen atmosphere until ahomogeneous solution is achieved. The solution is cooled to −3° C. and1.3 eq. of i-PrMgCl.LiCl in tetrahydrofuran is added. The reactionmixture is agitated at 0° C. until the formation of the mono-Grignard iscomplete as determined by HPLC analysis. Next, a solution of 1.1 eq. of3-chloro-2-fluorobenzaldehyde in tetrahydrofuran is added. This mixtureis allowed to stir at 0° C. until the formation of Compound 15a iscomplete by HPLC. Next, additional i-PrMgCl.LiCl solution intetrahydrofuran (2.5 eq.) is added and the reaction mixture is warmed toabout 20° C. After conversion to the second Grignard intermediate iscomplete, the reaction mixture is cooled to 3° C. Anhydrous CO₂ (g) ischarged to the reaction mixture at about 5° C. The reaction mixture isadjusted to about 20° C. After the carboxylation reaction is complete byHPLC, the reaction mixture is cooled to about 10° C. and water ischarged to quench the reaction followed by the addition of concentratedhydrochloric acid to adjust the pH to no more than 3. The reactionmixture is then warmed to about 20° C. The phases are separated. Theorganic phase is solvent exchanged to a mixture of isopropyl alcohol andwater and the resulting slurry is cooled to about 0° C. The product isisolated by filtration, washed with a mixture of isopropyl alcohol andwater and dried at about 40° C. to yield Compound 3.

Example 14 Alternative Preparation of Compound of Formula 4

Trifluoroacetic acid (10 eq.) is charged to a reactor and cooled to 0°C. Triethylsilane (1.5 eq.) is added maintaining the temperature<15° C.and the mixture agitated thoroughly. Compound 3 is added to thewell-stirred mixture in portions maintaining the temperature<15° C. Whenthe reaction is determined to be complete by HPLC, Compound 4 isprecipitated by adding a solution of 5 eq. sodium acetate in methanol(13 volumes) maintaining the temperature not more than 45° C. Warm theslurry to reflux and agitate for 2 to 3 h. The slurry is cooled to about0° C. and then agitated at that temperature for 2 to 3 h. The product isisolated by filtration, washed with methanol and dried at about 40° C.to yield Compound 4.

Example 15 Alternative Preparation of a Compound of Formula 9a

Compound 6a is combined with dimethylformamide (1.9 vol.),

N,N-dimethylformamide dimethyl acetal (1.1 eq.) and glacial acetic acid(0.026 eq.) before being warmed to about 65° C. The reaction ismonitored by HPLC. Once the reaction is complete the mixture is cooledto about 22° C. before (S)-2-amino-3-methyl-1-butanol (1.1 eq.) andtoluene (1.2 volumes) are added. The reaction is monitored by HPLC. Oncethe reaction is complete the mixture is concentrated. The residue iscombined with potassium chloride (0.5 eq) andN,O-bis(trimethylsilyl)acetamide (2.5 eq.) and warmed to about 100° C.The reaction is monitored by HPLC. Once the reaction is complete themixture is cooled and dichloromethane (6 vol.) is added. Aqueoushydrochloric acid is added to desilylate the product. This reaction ismonitored by TLC. Once the reaction is complete the organic phase iswashed with water, aqueous sodium bicarbonate and water. The solvent isexchanged for acetonitrile and the mixture is warmed to form a solution.The mixture is seeded and cooled to crystallize Compound 9a. The productis filtered, washed with cold acetonitrile and dried at NMT 40° C. toyield Compound 9a.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A compound selected from a compound of formula15:

or a salt thereof and a compound of formula 16


2. A compound of claim 1, which is a salt of formula 15a


3. A method comprising metalating a compound of formula 14:

and treating with 3-chloro-2-fluorobenzaldehyde to provide to provide acompound of formula 15:

or the salt thereof.
 4. The method of claim 3 further comprisingconverting the compound of formula 15 or the salt thereof to a compoundof formula 3:

or a salt thereof.
 5. The method of claim 4 wherein the compound offormula 15 is converted to the compound of formula 3 by metalating thecompound of formula 15 and treating with carbon dioxide to provide thecompound of formula
 3. 6. The method of claim 5 further comprisingconverting the compound of formula 3 or the salt thereof to a compoundof formula 4:

or a salt thereof.
 7. The method of claim 6 further comprisingconverting the compound of formula 4 or the salt thereof to a compoundof formula 5′:

or a salt thereof, wherein R_(c) is a leaving group.
 8. The method ofclaim 7 wherein R_(c) is halo or 1-imidazolyl.
 9. The method of claim 8wherein the compound of formula 5′ is a compound of formula 5a:


10. The method of claim 9 wherein the compound of formula 4 is convertedto the compound of formula 5a by treatment with1,1′-carbonyldiimidazole.
 11. The method of claim 10 further comprisingconverting the compound of formula 5′ or a salt thereof, to a compoundof formula 6:

or a salt thereof, wherein R is C₁-C₆alkyl.
 12. The method of claim 11wherein the compound of formula 5′ is converted to the compound offormula 6 by treatment with the corresponding mono-alkylmalonate salt.13. The method of claim 11 wherein R is ethyl.
 14. The method of claim13 wherein the compound of formula 5′ is converted to the compound offormula 6 by treatment with potassium monoethylmalonate.
 15. The methodof claim 11 further comprising converting the compound of formula 6 or asalt thereof, to a compound of formula 7:

wherein R_(a) and R_(b) are each independently C₁-C₆alkyl.
 16. Themethod of claim 15 wherein the compound of formula 6 is converted to thecompound of formula 7 by treatment with N,N-dimethyformamide dimethylacetal.
 17. The method of claim 16 wherein the treatment withN,N-dimethyformamide dimethyl acetal is carried out in the presence ofacetic acid at a temperature of about 100±50° C.
 18. The method of claim15 further comprising converting the compound of formula 7 to a compoundof formula 8:


19. The method of claim 18 wherein the compound of formula 7 isconverted to the compound of formula 8 by treatment with(S)-2-amino-3-methyl-1-butanol.
 20. The method of claim 18 furthercomprising converting the compound of formula 8 to a compound of formula9:


21. The method of claim 20 wherein the compound of formula 8 isconverted to the compound of formula 9 by treatment with potassiumchloride and N,O-bistrimethylsilylacetamide.
 22. The method of claim 20further comprising converting the compound of formula 9 to a compound offormula 10:


23. The method of claim 22 wherein the compound of formula 9 isconverted to the compound of formula 10 by treatment with a base.